WO2010142827A1 - Propriétés neuroprotectrice de la 5'-méthylthioadénosine - Google Patents

Propriétés neuroprotectrice de la 5'-méthylthioadénosine Download PDF

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WO2010142827A1
WO2010142827A1 PCT/ES2010/070374 ES2010070374W WO2010142827A1 WO 2010142827 A1 WO2010142827 A1 WO 2010142827A1 ES 2010070374 W ES2010070374 W ES 2010070374W WO 2010142827 A1 WO2010142827 A1 WO 2010142827A1
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mta
disease
pharmaceutically acceptable
acceptable salts
prodrugs
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Spanish (es)
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Pablo VILLOSLADA DÍAZ
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Proyecto de Biomedicina CIMA SL
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Priority to JP2012514499A priority Critical patent/JP2012529477A/ja
Priority to CN2010800355935A priority patent/CN102573854A/zh
Priority to CA2762890A priority patent/CA2762890A1/fr
Priority to MX2011013311A priority patent/MX2011013311A/es
Priority to EP10730196A priority patent/EP2441459A1/fr
Priority to AU2010258589A priority patent/AU2010258589A1/en
Priority to US13/376,894 priority patent/US20120083464A1/en
Publication of WO2010142827A1 publication Critical patent/WO2010142827A1/fr
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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Definitions

  • the present invention is applied in the area of therapeutic agents for neurological, psychiatric and aging disorders.
  • it refers to the neuroprotective effect of the small 5'-methylthioadenosine molecule.
  • Aging and neurological and psychiatric disorders cause damage and death to nerve cells.
  • Frequent and relevant lesions of the nervous system include, but are not limited to, neuronal degeneration, ischemia, inflammation, immune responses, trauma and cancer.
  • nerve cells can die within a few minutes or hours or survive this initial injury in a damaged state that activates neurodegeneration, also ending in cell death.
  • Neuroprotection is aimed at the conservation, recovery, cure or regeneration of the nervous system, its cells, structure and function (Vajda et al. 2002, J Clin Neurosci 9: 4-8).
  • An objective of neuroprotection is to prevent or minimize the effects of an original injury to the nervous system, or to prevent or minimize the consequences of harmful endogenous or exogenous processes that cause damage to axons, neurons, synapses and dendrites.
  • treatment strategies are often based on the modulation of a single proposed injury factor.
  • neuropreceptor drugs that include the following classes are under investigation: an ⁇ ün ⁇ lamato ⁇ os agents, antagonists of N-methyl D-aspartate f ⁇ N MDA), a-amino-3-hydr ⁇ xi-5 -meeller-4-isoxazul propionic acid ( ⁇ MP ⁇ ), ckxanabinol, sodium channel bluijucadorcs, tro ⁇ ropin-releasing hormone (TRHT), growth factors, glucocorychoidcs, eafeinol, opioid antagonists, apoptosis inhibitors, free radical trappers / kidnappers, eritr ⁇ poyeüna. Jc calcium channel blockers, magnesium suffrage, statues.
  • MTAj is a sulfop-containing adenine HpofiJico nucidose, produced from S-adenosylmethionine (SAM) during the synthesis of spermine and spermidine poiiammas.
  • SAM S-adenosylmethionine
  • MTA exhibits immunomodulatory activity by suppressing the production of proinflammatory genes and cytokines (interferon- ⁇ , tumor necrosis factor ⁇ and inducible nitric oxide synthase) and increasing the production of anti-inflammatory cytokines (interleukin-10) ; and the inversion of cerebral autoimmune disease; thus suggesting beneficial effects for multiple sclerosis and other autoimmune diseases (Moreno et al. Diss. Abstr. Int., C 2007, 68 (1), 111; Ann Neurol 2006; 60: 323-334).
  • WO2006097547 describes MTA for use in the prevention and / or treatment of autoimmune diseases, such as multiple sclerosis (MS) and in the prevention and / or treatment of transplant rejection.
  • EP 526866 (Bioresearch SpA) describes that adenosine compounds are suitable for therapeutic use in various situations of ischemia, such as cases of cerebral or myocardial ischemia or for ischemia of any type of organ or tissue.
  • ischemia such as cases of cerebral or myocardial ischemia or for ischemia of any type of organ or tissue.
  • ⁇ vila et al. Int J Biochem CeIl Biol. 2004; 36 (11): 2125-30), the authors suggest that MTA can perform cellular processes in many ways, influencing numerous critical cell responses, including the regulation of gene expression, the proliferation, differentiation and apoptosis. They propose a therapeutic potential for MTA due to observations in liver damage and cancer models.
  • MTA is indeed effective in protecting astrocytes and neurons of the cerebral cortex deprived of oxygen and glucose; in the protection of neurons of the hippocampus Cornu Ammonis (CAl) with respect to cell death after a global ischemia; in the protection of oligodendrocytes with respect to excitotoxicity and damage to the optic nerve tissue after ischemia; in the protection of a glial neuronal cell culture subjected to excitotoxicity; in the decrease in the number of dystrophic axons and in the prevention of the loss of myelin and axons.
  • CAl Cornu Ammonis
  • the present invention relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the prevention or treatment of death or damage of nerve cells.
  • the present invention relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the prevention or treatment of death or nerve cell damage.
  • the present invention also relates to a method of prevention or treatment of death or damage of nerve cells comprising administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs of the same.
  • the present invention also relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a neuroprotective drug.
  • the present invention also relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use as a neuroprotective drug.
  • the present invention relates to a neuroprotection method comprising administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof.
  • the present invention further relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the regeneration of nerve cells.
  • the present invention also relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the regeneration of nerve cells.
  • the present invention also relates to a method of regenerating nerve cells comprising administering to an individual in need thereof an effective amount of MTA of one of its pharmaceutically acceptable salts and / or prodrugs thereof.
  • the present invention further relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the prevention or treatment of a neurological or psychiatric disease.
  • the present invention also relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the prevention or treatment of a neurological or psychiatric disease.
  • the present invention also relates to a method of prevention or treatment of a neurological or psychiatric disease comprising administering to an individual in need thereof an effective amount of MTA of one of its pharmaceutically acceptable salts and / or prodrugs of the same. Dcscripciés ⁇ of the figures
  • FIG. 1 MTA toxicity profile in mixed cultures of neurons and astrocytes of the cerebral cortex.
  • the toxicity profile of MTA shows that the compound is safe at the concentrations analyzed in mixed cultures of neurons and astrocytes of the cerebral cortex.
  • LDH Lactate dehydrogenase
  • FIG. 2 MTA protects against simulated ischemia in mixed cultures of neurons and astrocytes obtained from the cerebral cortex. Damage induced by oxygen and glucose deprivation (OGD) and protection by MTA in mixed cultures of neurons and astrocytes obtained from the cerebral cortex.
  • IAA iodoacetate
  • Fig. 2A or 2B iodoacetate
  • 2R 2R -amino-5-phosphonovaleric acid
  • 10 ⁇ M MTA that was even more protective than APV (50 ⁇ M). * or # p ⁇ 0.05; ** or ## p ⁇ 0.01.
  • FIG. 3 MTA treatment of rats after focal ischemia. MTA does not protect from brain tissue damage after 90 minutes of occlusion of the middle cerebral artery (MCAO). Treatment with MTA began 30 minutes after the onset of ischemia (ip, twice daily). The rats were sacrificed after three days of reperfusion, cut into sheets and stained with 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) to observe the damaged region. Values represent the mean ⁇ Standard Error of the mean (SEM) of the damaged area.
  • Figure 4 MTA treatment of rats after global ischemia. MTA protects the neurons of the CAl hippocampus from cell death after 10 minutes of global ischemia. MTA treatment was started 30 minutes after ischemia (ip, twice daily). The rats were sacrificed 7 days after reperfusion, sectioned and stained with Fluoro-jade to observe the dying cells. The values represent the average
  • FIG. 5 Profile of toxicity of MTA in oligodendrocytes and protection of excitotoxic lesions. Toxicity profile of MTA in cultured oligodendrocytes derived from the optic nerve (A).
  • A Toxicity profile of MTA in cultured oligodendrocytes derived from the optic nerve
  • B MTA protects oligodendrocytes from low intensity excitotoxic lesions with AMPA (10 ⁇ M). However, it does not protect oligodendrocytes from death at high doses of AMPA (100 ⁇ M).
  • FIG. 6 MTA protects against simulated ischemia in optic nerves. The damage induced by
  • OGD in the isolated optic nerve was attenuated by receptor antagonists of
  • Figure 7 Evolution over time of NMDA-mediated neurotoxicity in a pure neuronal culture. The data represent the mean + s.e. of 12 experiments. *** p ⁇ 0.01 compared to the vehicle.
  • Figure 8 NMDA-mediated concentration-response curve of neurotoxicity in a pure neuronal culture. The data represent the mean + s.e. of 12 experiments. *** p ⁇ 0.01 compared to the vehicle.
  • NMDA in a pure neuronal culture The data represent the mean + s.e. of 12 experiments.
  • FIG. 11 Absence of the effect of MTA (100 to 500 ⁇ M) in the increase in caspase 3 activity mediated by NMDA in a pure neuronal culture.
  • the data represent the mean + s.e. of 12 experiments.
  • Figure 12 Effect of MTA (250 ⁇ M) the increase in caspase 3 activity mediated by
  • NMDA in a mixed culture of neuronal and glial cells.
  • the data represent the mean + s.e. of 12 experiments.
  • Figure 13a Neuroinflammation model in cerebellar organotypic cultures.
  • LPS lipopolysaccharides
  • Cerebellar organotypic cultures treated with 15 ⁇ g / ml of LPS showed axonal swelling (arrows in panel i) and axonal transection (arrow heads in panel i) absent in control and in organotypic cultures treated with 5 ⁇ g / ml of LPS .
  • Figure 13b Activation of microglia in organotypic culture of mouse cerebellum.
  • ILl-beta concentration Measured by ELISA LPS treatments induce a release in the medium that reaches the maximum at 3 hours. Treatment with MTA induces a release of a smaller amount of IL-beta at 3 hours.
  • Figure 15 Clinical assessment of C57B6 mice suffering from chronic EAE and treated with MTA after the onset of the disease.
  • Day 1 first day with an EAE rating of 2 or higher; Placebo (black squares), MTA 96 ⁇ Mol / Kg (white squares).
  • Figure 16 Quantification of axonal density (as described in the methods) in animals treated with placebo (black) or MTA (white) in the two locations of the spinal cord (cervical and lumbar spinal cord).
  • FIG. 17 Representative examples of NeuN immunoreactivity of the hippocampus at 30 days after pilocarpine-induced epileptic status (SE) in adult rats treated with the MTA pre-SE (A), MTA post-SE (B) or vehicle ( C).
  • A the subject with pre-SE MTA shows a good conservation of neurons in the dentate gyrus and the pyramidal cell layer, while the rat in the post-SE MTA group shows only a slight cellular loss in the dentate gyrus (arrow in B).
  • the control shows a severe cell loss in both the dentate gyrus and the pyramidal cell layer of the CAl (C) area.
  • FIG. 19 Effect of MTA on the survival of dopaminergic neurons (TH cells) in the animal model of Parkinson's disease, C57B6 mice treated with MPTP. Control animals have a normal density of TH cells in their black substance. Animals treated with MPTP have a 40% decrease in the number of TH neurons compared to controls. In contrast, animals treated with MTA (96 ⁇ M) after being exposed to MPTP have a non-significant reduction in the number of TH neurons compared to controls (10%) and a significantly higher number of TH neurons than animals with MPTP Figure 20. Effect of MTA on neuronal differentiation. A) PC 12 cells treated for 4 days with NGF (100 ng / ml) or MTA at different concentrations. Differences in the development of neurites with the different treatments are observed. B) Quantification of neurites in cells
  • PC 12 treated with NGF (100 ng / ml) or different concentrations of MTA for 4 days. The results are expressed as a percentage of differentiation with respect to the control with NGF.
  • Figures 21A, 21B, 21C Quantification of the percentage of phosphorylation of different intracellular proteins in PC 12 cells treated with NGF (100 ng / ml) or MTA at different concentrations for 4 days using Luminex technology.
  • FIG. 22 Percentage of cell viability (MTT assay) in RN22 cells exposed to stress with copper sulfate (150 ⁇ M) and treated with NGF (100 ng / ml) or MTA at different concentrations for 24 hours.
  • Figure 23 Determination of ROS levels in RN22 cells exposed to stress with copper sulfate (150 ⁇ M) and treated with NGF (100 ng / ml) or MTA at different concentrations during different times.
  • FIG. 24 Percentage of cell viability (MTT assay) in RN22 cells exposed to stress with hydrogen peroxide (100 ⁇ M) and treated with MTA at different concentrations during
  • Figure 25 Determination of ROS levels in RN22 cells exposed to stress with hydrogen peroxide (100 ⁇ M) and treated with MTA at different concentrations during different times.
  • the present invention relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the prevention or treatment of death or damage of nerve cells.
  • the present invention relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the prevention or treatment of death or nerve cell damage.
  • the present invention also relates to a neuroprotection method comprising administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof.
  • the present invention also relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a neuroprotective drug.
  • the present invention also relates to
  • the present invention also relates to a method of prevention or treatment of death or nerve cell damage that it comprises administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof.
  • MTA which is also referred to herein as 5'-methylthioadenosine
  • 5'-methylthioadenosine is a commercial product that can be provided, for example by the Sigma company.
  • this compound can be obtained by methods known to one skilled in the art, for example, from S-adenosylmethionine (SAM) according to the procedure described by Schlenk F. et al., Arch. Biochem. Biophys., 1964, 106: 95-100.
  • SAM S-adenosylmethionine
  • the CAS registration number of MTA is 2457-80-9, and its structural formula is:
  • prodrug includes any compound derived from MTA, for example, ester, amide, phosphate, etc., which, after being administered to an individual, is capable of providing MTA or pharmaceutically acceptable salt thereof, directly or indirectly, to said individual.
  • said derivative is a compound that increases the bioavailability of MTA when administered to an individual or that induces the release of MTA in a biological compartment.
  • the nature of said derivative is not critical, as long as it can be administered to an individual and that it provides MTA in a biological compartment of the individual.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • MTA prodrugs can be prepared in a practical manner, for example, by binding a progroup to one or both hydroxyl groups of the ribose ring.
  • An example of an MTA prodrug is 2 '- [(2Z) -3- (4-hydroxyphenyl) -2-methoxy-2-propenoate] -3'- [(2E) -3- (lH-imidazol-4- il) -2-propenoate] -5'-S-methyl-5'-thio-adenosine (Journal of Medicinal Chemistry, 47 (9): 2243-2255, 2004).
  • Another example of a prodrug or precursor of MTA is S-adenosylmethionine (SAM).
  • SAM S-adenosylmethionine
  • pharmaceutically acceptable means that a compound or combination of Compounds are sufficiently compatible with the other components of a formulation, and are not harmful to the patient to levels acceptable by industry standards.
  • 5'-methylthioadenosine salts are those in which the counterion is pharmaceutically acceptable.
  • salt as mentioned in the present invention is intended to comprise any stable salt that the MTA is capable of forming.
  • Pharmaceutically acceptable salts are preferred. Salts that are not pharmaceutically acceptable are also within the scope of the present invention, since they refer to intermediates that may be useful in the preparation of compounds with pharmacological activity.
  • the salts can be obtained in a practical way by treating the basic form of
  • MTA with said appropriate acids, such as inorganic acids, such as hydro acids, for example, hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie, ethanedioic), malonic, succinic (ie, butanedioic acid), maleic, fumaric, malic (i.e., hydroxybutanedioic acid) ), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.
  • inorganic acids such as hydro acids, for example, hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phospho
  • Pharmaceutically acceptable salts may be obtained by treating the basic form of MTA with such appropriate pharmaceutically acceptable acids, such as inorganic acids, for example, hydro acids, including hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1, 2,3-propane-tricarboxylic, methanesulfonic acid , ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic or similar acids.
  • inorganic acids for example, hydro acids, including hydrochloric, hydrobromic and the like
  • sulfuric acid nitric acid
  • salt form can be converted by alkali treatment into the free basic form.
  • prevention refers to preventing it from occurring, that there is or alternatively delays the occurrence or recurrence of a disease, disorder or condition to which said term applies, or of one or more symptoms associated with a disease, disorder or condition.
  • prevention refers to the act of prevention, as defined “to prevent” immediately before.
  • treat refers to reversing, alleviating, or inhibiting the progress of the disorder or condition to which said term applies, or one or more. symptoms of such disorders or conditions.
  • treatment refers to the act of treating, as defined “treating” immediately before.
  • subject means animals, particularly mammals, such as dogs, cats, cows, horses, sheep, geese and humans. Particularly preferred subjects are mammals, including humans of both sexes.
  • an "effective amount" of MTA and pharmaceutically acceptable salts thereof may be in the range of 0.01 mg to 50 g per day, 0.02 mg to 40 g per day, 0.05 mg to 30 g per day, 0.1 mg to 20 g per day, 0.2 mg to 1 g per day, 0.5 mg to 5 g per day, 1 mg to 3 g per day, 2 mg to 2 g per day, 5 mg to 1.5 g per day, 10 mg to 1 g per day, 10 mg to 500 mg per day.
  • Nerve cells include those cells from any region of the brain, spinal cord, optic nerve, retina and peripheral ganglia.
  • Neurons include those of a human embryonic, fetal or adult neuronal tissue, including hippocampal, cerebellum, spinal cord, including hippocampal tissue, cerebellum, spinal cord, cortex (e.g., motor or somatosensory cortex), striatum, forebrain ( cholinergic neurons), ventral midbrain (black matter cells) and the locus ceruleus (neuroadrenaline cells of the central nervous system).
  • MTA its pharmaceutically acceptable salts and / or prodrugs thereof can be used for the prevention or treatment of one or more, preferably two or more, pathological or harmful conditions related to death or nerve cell damage selected from, but not limited to, chemical substances, such as oxidative stress conditions, toxic substances, infectious organisms, radiation, traumatic lesions, hypoxia, ischemia, abnormally folded abnormal proteins, excitotoxins, free radicals, reticulum stressors endoplasmic, mitochondrial stressors, including, but not limited to, electron transport chain inhibitors, Golgi apparatus antagonists, axonal damage or loss, demyelination, inflammation, neuronal pathological outbreak (attacks). Also preferably, the uses and methods of the present invention are directed to prevent or treat death or damage of nerve cells regardless of the cause.
  • chemical substances such as oxidative stress conditions, toxic substances, infectious organisms, radiation, traumatic lesions, hypoxia, ischemia, abnormally folded abnormal proteins, excitotoxins, free radicals, reticulum stressors endo
  • neuroprotective refers to the ability to prevent or reduce death or damage to nerve cells, including neurons and glial cells, or the rescue, resuscitation or reactivation of cells.
  • nervous for example, after pathological or harmful conditions in the brain, central nervous system or peripheral nervous system. Therefore, this neuroprotective effect comprises the conferred ability of neuronal cells to maintain or recover their neuronal functions. Stabilize the cell membrane of a neuronal cell or helps in the normalization of the functions of neuronal cells. Prevents loss of viability or functions of neuronal cells. It includes the inhibition of the progressive deterioration of neurons that leads to cell death. It also refers to any detectable protection of neurons with respect to stress.
  • Neuroprotection includes the regeneration of nerve cells, that is, the regrowth of a population of nerve cells after illness or trauma.
  • Disease-modifying drugs These disease-modifying drugs contrast with the symptomatic therapy that is commonly used for such diseases, but does not change the evolution of the disease.
  • a neuroprotective drug is a Disease Modifying Drug (DMD) for the treatment of brain diseases.
  • DMD Disease Modifying Drug
  • the present invention relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the regeneration of nerve cells.
  • the present invention relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the regeneration of nerve cells.
  • the present invention relates to a method of regeneration of nerve cells comprising administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof.
  • Neuroprotection can be determined directly, for example, by measuring the delay or prevention of neuronal death, such as, for example, by reducing the number of apoptotic neurons in cerebrocortical cultures after stress. Neuroprotection can also be determined directly, for example, by measuring the severity or extent of damage to a tissue or organ of the nervous system, or the functional loss thereof, after such stress, such as, for example, by measuring the decrease in size of cerebral infarctions after occlusion of the middle cerebral arterial (MCAO) or reperfusion injury.
  • MCAO middle cerebral arterial
  • neuroprotection can be identified by magnetic resonance imaging (measurement of brain volume, tractography, N-acetyl-asparto levels by spectroscopy) or by obtaining retinal images with consistent optical imaging (thinning of the retinal nerve fiber layer) or retinal spectroscopy (levels of cytochrome c, oxyhemoglobin, lactate, glutamate, iNOS).
  • neuroprotection can be determined indirectly by detecting the activation of one or more biological mechanisms for the protection of neurons, including, without limitation, the detection of the activation of the Keapl / Nrf2 mechanism or the induction of one or more enzymes of phase 2, including, but not limited to, hemooxygenase-1 (HO-I).
  • Neural protection detection and measurement methods are provided in the following Examples and there are other methods known in the art.
  • Neurological diseases are those disorders of the central nervous system and peripheral nervous system, which include disorders of the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junctions and muscle.
  • Diseases of the central and peripheral nervous system include, without limitation, as knowledge in the advances of clinical manifestations, Absence of Septum Pellucidum, Acid Lipase Disease, Acid Maltase Deficiency, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Adié Pupil , Adié syndrome, Adrenoleukodystrophy, Agenesis of Corpus Callosum, Agnosia, Aicardi syndrome, Aicardi-Goutieres syndrome, AIDS - Neurological complications, Alexander disease, Alpers disease, Alternating hemiplegia, Alzheimer's disease, Amyotrophic lateral sclerosis, Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Antiphospholipid Syndrome, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation, Arteriovenous Malformation, Asperger Syndrome, Ataxia, Telangiectasia
  • Psychiatric disorders include those indicated by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) published by the American Psychiatric Association, and covers all mental health disorders for children and adults.
  • psychiatric disorders include a disorder selected from Acute Stress Disorder; Adaptation Disorder Not specified; Anxiety Adjustment Disorder; Adaptation Disorder with Depressive Humor; Adaptation disorder with behavior disorder; Adaptation Disorder with Mixed Anxiety and Depressive Humor; Adaptation Disorder with Mixed Alteration of Emotions and Behavior; Agoraphobia without a History of Panic Disorder; Nervous Anorexia; Antisocial Personality Disorder; Anxiety Disorder Due to a medical condition; Anxiety Disorder, NOS; Avoiding Personality Disorder; NOS bipolar disorder; Bipolar I Disorder, Most Recent Depressive Episode, In Total Remission; Bipolar I Disorder, Most Recent Depressive Episode, In Partial Remission; Bipolar I Disorder, Most Recent Depressive Episode, Mild; Bipolar I Disorder, Most Recent Depressive Episode, Moderate; Bipolar I Disorder
  • the subject suffers from a neurological disease (selected from multiple sclerosis, progressive multiple sclerosis, Parkinson's disease, Alzheimer's disease, optic neuromyelitis, neuroinflammation, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Dementia with Lewy bodies, spinal muscular atrophy, cerebral ischemia, global cerebral ischemia, optic nerve ischemia, optic neuritis, brain tumor, head trauma and epilepsy, encephalopathy, encephalitis, meningitis, chronic pain, migraine, headache, chronic fatigue and fibromyalgia) or a psychiatric illness (selected from depression, bipolar disorder, schizophrenia, obsessive compulsive illness, alcohol abuse, drug abuse).
  • a neurological disease selected from multiple sclerosis, progressive multiple sclerosis, Parkinson's disease, Alzheimer's disease, optic neuromyelitis, neuroinflammation, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington'
  • MTA, its pharmaceutically acceptable salts and / or prodrugs thereof can be used as a first line or initial therapy to prevent or treat death or nerve cell damage.
  • MTA, its pharmaceutically acceptable salts and / or prodrugs thereof can be used as an adjuvant or as an additive therapy to other drugs in a subject that is already being treated for a specific neurological or psychiatric disease, for example, as an addition to an existing treatment against epilepsy in patients with partial seizures (epileptic seizures that begin in a specific part of the brain). It can be used in patients with and without secondary generalization (where the attack subsequently extends to the entire brain).
  • MTA in the uses and methods of neuroprotection or prevention or treatment of death or damage of nerve cells or regeneration of nerve cells, MTA, its pharmaceutically acceptable salts and / or pro drugs thereof are used as adjuvants or additional therapy to a subject with a neurological or psychiatric disease.
  • MTA in the various uses and methods of neuroprotection or prevention or treatment of death or damage of nerve cells or regeneration of nerve cells, MTA, its pharmaceutically acceptable salts and / or pro drugs of they are administered to a healthy subject, preferably a healthy subject older than 18 years, more preferably a healthy subject older than 45 years, even more preferably a healthy subject older than 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years.
  • a healthy subject is intended to understand its common meaning, as well as to subjects who may suffer from one or more pathological conditions other than a disease. Neurological or psychiatric.
  • MTA in the various uses and methods of neuroprotection or prevention or treatment of death or damage of nerve cells or regeneration of nerve cells, MTA, its pharmaceutically acceptable salts and / or prodrugs thereof are used. as adjuvants or additional therapy for a subject being treated with one or more neuropotentiating drugs.
  • Neuropotentiating drugs include those that improve learning and memory, attention, humor, communication skills and sexual performance.
  • Examples of neuropotentiating drugs are those that direct long-term synaptic potentiation (LTP) or long-term depression (LTD), modulation of calcium channels, or cAMP response element binding protein (CREB).
  • CAMP is the acronym for cyclic adenosine monophosphate.
  • Particular examples of neuropotentiating drugs are phosphodiesterase inhibitors, such as rolipram; donepezil; NMDA receptor agonists for glutamate, such as D-cycloserine; ampaquines; modafinil; methylphenidate
  • the present invention also relates to the use of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof as an active ingredient in the manufacture of a medicament for the prevention or treatment of a neurological or psychiatric disease.
  • the present invention also relates to MTA, its pharmaceutically acceptable salts and / or prodrugs thereof for use in the prevention or treatment of a neurological or psychiatric disease.
  • the present invention also relates to a method of prevention or treatment of a neurological or psychiatric disease comprising administering to an individual in need thereof an effective amount of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof.
  • the neurological or psychiatric disease can be any of those indicated above.
  • the neurological or psychiatric disease is selected from optic nerve ischemia, progressive multiple sclerosis, optic neuromyelitis, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Friedreich's ataxia, Huntington's disease, Lewy body dementia , spinal muscular atrophy, epilepsy, optic neuritis, head trauma, brain tumor, depression, bipolar disorder, schizophrenia, obsessive compulsive disease, alcohol abuse, drug abuse, encephalopathy, encephalitis, meningitis, chronic fatigue, fibromyalgia, chronic pain, migraine , and headache.
  • MTA its pharmaceutically acceptable salts and / or prodrugs thereof can be formulated in various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions commonly used for the systematic administration of drugs, for example, any solid composition (for example, tablets, capsules, granules, etc.) or liquid composition (for example, solutions, suspensions, emulsions, etc.).
  • a pharmaceutically acceptable carrier which can take a wide variety of forms depending on the form of the desired preparation for administration.
  • These pharmaceutical compositions are desirable in the form of unit doses suitable, particularly, for oral, rectal, percutaneous, intrathecal, intravenous administration or by parenteral injection.
  • any of the usual pharmaceutical means can be used, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers, such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, tablets, capsules and tablets. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case obviously pharmaceutical solid carriers are used.
  • the carrier usually comprises sterile water, at least in large part, although other ingredients may be included, for example, to aid in solubility.
  • Injectable solutions can be prepared, for example, where the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose solution.
  • Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be used. Also included are preparations in solid form, which are intended to become, shortly before use, preparations in liquid form.
  • the carrier optionally comprises a penetration enhancing agent or a suitable wetting agent, or both, optionally combined with suitable additives of any nature in minor proportions, whose additives do not introduce a significant detrimental effect on the skin.
  • the unit dosage form as used in the present invention refers to physically discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect associated with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and multiple thereof in a segregated manner.
  • compositions according to the present invention may contain the active ingredient in an amount that is in the range of about 0.1% to 70%, or about 0.5% to 50%, or about 1% a
  • the dose of MTA, its pharmaceutically acceptable salts and / or prodrugs thereof to be administered depends on the individual case and, as usual, must be adapted to the conditions of the individual case for optimum effect. Therefore, it depends, of course, on the frequency of administration and the potency and duration of action of the compound used in each case for therapy or prophylaxis, but also on the nature and severity of the disease and symptoms, and on the sex, age, weight, co-medication and individual sensitivity of the subject to be treated and whether the therapy is acute or prophylactic. Doses can be adapted based on weight and for pediatric applications. Daily doses can be administered q.d. or in multiple quantities, such as b.i.d., t.i.d. or q.i.d.
  • Example 1 Effect of MTA in a model of ischemia in neuronal culture
  • MTA neuroprotective potential of MTA was explored in a neuronal ischemia model in which astrocytes and neurons were co-cultured.
  • astrocytes and neurons of the cerebral cortex of rats were used. The cells were deprived of oxygen and glucose and the protective effects of MTA were measured.
  • Ischemic damage was induced by incubating cell cultures in a hyperbaric chamber for 1 hour in saturated nitrogen buffer containing 130 mM NaCl, KCl
  • the cells were incubated in normoxia, glucose was added and the iodoacetate was removed for an additional period of 24 hours. MTA or the NMDA APV receptor antagonist (50 ⁇ M) was added during ischemia to assess its neuroprotective activity. The cell viability and cell death of the cultures were analyzed as indicated above. The results are expressed as the mean ⁇ SEM of at least four independent experiments performed in triplicate.
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • ischemia was mimicked by the removal of oxygen and glucose (OGD) from the culture medium and the addition of iodoacetate (a glycolytic block; IAA). Ischemia-induced damage was reduced by MTA in mixed cultures of neurons and astrocytes obtained from the cerebral cortex ( Figure 2). Two ischemia conditions were tested using IAA at 20 or 50 ⁇ M (left and right, respectively).
  • OGD oxygen and glucose
  • MTA protects against simulated ischemia in mixed cultures of neurons and astrocytes obtained from the cerebral cortex.
  • Example 2 Effect of MTA in a rat model of global ischemia
  • mice Young male Wistar rats (200-250 g) were used. After ischemia, the animals were treated with MTA as described below.
  • the rats were fasting all night.
  • the rats underwent occlusion of the middle cerebral artery (MCAO) for 90 minutes using the intraluminal filament model as previously described.
  • MCAO middle cerebral artery
  • frontal lobe ischemia bilateral loss of straightening reflex, leg extension and mydriasis. Rectal and body temperature was maintained at 37 ° C during surgery and ischemia with a heat pad. Animals that did not completely lose their straightening reflexes or who developed seizures after carotid artery occlusion were excluded from the study. Treatment
  • the animals were treated with MTA (30 or 100 mg / kg i.p.), twice daily reconstituted in 300 mM Tris, or placebo (300 mM Tris) starting at 30 min from the onset of ischemia.
  • MTA 5'-deoxy-5'-methylthioadenosine
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • MTA protects CAl hippocampal neurons from cell death after 10 min of global ischemia.
  • Example 3 Effect of MTA on the excitement toxicity of oligodendrocytes and optic nerve ischemia
  • the neuroprotective potential of MTA was explored in an excitotoxicity oligodendrocyte model and a white matter ischemia model
  • Oligodendrocytes were cultured from optic nerves of perinatal rats.
  • the cells were exposed to excitotoxins and the protective effects of MTA were measured.
  • Optic nerves The entire optic nerves of young rats were isolated and subjected to experimental ischemia.
  • the cells were seeded in 24-well plates carrying 12 mm diameter coverslips coated with poly-D-lysine (10 ⁇ g / ml) at a density of 5 x 10 cells per well.
  • the cells were maintained at 37 ° C and 5% CO 2 in a chemically defined medium
  • MTA the cells of 2-4 days in the culture were exposed for 24 hours to the drug and the cell viability was evaluated using calcein-AM (Invitrogen).
  • calcein-AM Invitrogen
  • the cells were pre-incubated with MTA for 15 minutes and then exposed to AMPA for an additional period of 15 minutes. Twenty-four hours after drug application, cell viability was evaluated using calcein-AM
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • the toxicity profile of MTA (1 ⁇ M-3 mM) was evaluated in cultures of oligodendrocytes exposed to the compound for 24 hours, evaluated with fluorescence of calcein-AM. The results indicated that significant toxicity was observed at concentrations of MTA above ( Figure 5A).
  • the potential protection of MTA from excitotoxic lesions to oligodendrocytes induced by selective activation of ionotropic glutamate receptors of the AMPA type was examined under experimental conditions in which MTA was not toxic to cells (100-300 ⁇ M). At agonist concentrations that induce apoptosis or necrosis (10 ⁇ M of AMPA), the MTA exerted a robust protective activity (Figure 5B). In contrast, no protection was observed under conditions that caused the necrotic death of oligodendrocytes (AMPA at 100 ⁇ M; Figure 5B).
  • MTA protects oligodendrocytes from excitotoxicity and damage to optic nerve tissue after experimental ischemia.
  • MTA does not show any neuroprotection against a neurotoxic lesion in a pure neuronal culture.
  • a protective action indicated by blocking caspase 3 activation was observed in a mixed glial-neuronal culture. This suggests that glial cells may be necessary in the neuroprotective action of MTA in neuroexcitotoxicity.
  • nNMDA neuroprotective effect of MTA has been studied using an exposure model similar to excitotoxicity to the NMDA glutamate NMDA receptor agonist.
  • the neurotoxicity of nNMDA was studied in two models: 1) pure rat cortical neuronal culture and 2) mixed glial-cortical neuronal culture (Nicoletti et al., 1999, Neuropharmacology, 38: 1477-
  • cortical neurons Primary cultures of cerebral cortical neurons were prepared essentially as previously described (Bruno et al., 2001, Eur. J. Neurosci., 13: 1469-1478). Fronto-lateral cortical lobes were dissected from Sprague-Dawley 17-day embryonic fetuses and mechanically dissociated in Hank's balanced solution. The cortical lobes were crushed by aspiration 7-10 times using a Pasteur pipette with a tip narrowed to the fire.
  • the cells were resuspended in serum-free neurobasal medium (GIBCO) supplemented with B27 (GIBCO) containing 2 mM L-glutamine, penicillin (20 units / ml) and streptomycin (5 ⁇ g / ml) and were placed on 24-well culture plates coated with poly-L-lysine or on 6-well culture plates coated with poly-L-lysine.
  • GEBCO serum-free neurobasal medium
  • B27 GIBCO
  • penicillin 20 units / ml
  • streptomycin 5 ⁇ g / ml
  • the cells were resuspended in serum-free neurobasal medium (GIBCO) supplemented with B27 (GIBCO) and 5% fetal bovine serum containing 2 mM L-glutamine, penicillin (20 units / ml) and streptomycin (5 ⁇ g / ml ) and were placed on 24-well culture plates coated with poly-L-lysine or on 6-well culture plates coated with poly-L-lysine.
  • the cells were maintained at 37 ° C in an atmosphere of saturated humidity containing 95% air and 5% CO 2 and cortical neurons were used for experiments after 7 days in vitro (DIV).
  • LDH test a test for experiments after 7 days in vitro (DIV).
  • cortical neurons or mixed cortical glial neurons or cells seeded on 24-well plates at a rate of 15 x 10 4 cells / well and cultured for 7 IVD, were treated vehicle (DMSO% or), NMDA (300 ⁇ M), NMDA (300 ⁇ M) + MTA (at different concentrations) or NMDA (300 ⁇ M) + MK-801 (10 ⁇ M) for 6 h and 24 h.
  • vehicle DMSO% or
  • NMDA 300 ⁇ M
  • NMDA 300 ⁇ M + MTA (at different concentrations)
  • NMDA (300 ⁇ M) + MK-801 (10 ⁇ M) for 6 h and 24 h.
  • the supernatants were collected and the cells were washed with PBS and used with 0.9% Triton X-IOO (v / v) in saline.
  • Lactate dehydrogenase (LDH) activity was measured as an index of cell death and mortality was expressed as the percentage of LDH released in the culture medium.
  • LDH was measured spectrophotometrically at 490 nm in a 96-well plate reader using the Cytotox 96 Kit according to the manufacturer's instructions (Promega). The percentage of LDH release is defined by the proportion of LDH released over the total LDH present in the cell at the beginning of treatment. All samples were made in triplicate (Posada et al., 2007, Br. J. Pharmacol, 150: 577-585). MTT test
  • cortical neurons seeded on 24-well plates at a rate of 15 x 10 4 cells / well and cultured for 7 IVD or SH-SY5Y neuroblastoma cells developed in 24-well culture plates until reaching a confluence 80% were treated with vehicle (DMSO l% o), NMDA (300 ⁇ M), NMDA (300 ⁇ M) + MTA (at different concentrations) or NMDA (300 ⁇ M) + MK-801 (10 ⁇ M) for 24 hours . After the incubation period, five mg / ml of MTT was added to each well, the volume of MTT added being equal to one tenth of the total volume of the well. This was followed by incubation at 37 0 C for 3 hours.
  • Cortical neurons or neurons and mixed cortical glial cells were placed on 6-well culture plates coated with poly-L-lysine and after 7 DIV, the cells were treated with vehicle or NMDA (300 ⁇ M) for different periods of time. In another group of experiments, the cells were treated with vehicle, NMDA alone or in the presence of MTA or MH-801 for 1 hour. The cells were then washed twice with cold PBS and used in lysis buffer containing 100 mM Hepes, 5 mM DTT, 5 mM EGTA, 0.04% Nonidet P-40, and 20% glycerol; pH 7.4.
  • the extracts were then centrifuged at 5,000xg for 10 min at 4 ° C, and the protein content was determined by using the BCA protein assay according to the manufacturer's instructions.
  • Cell extracts were incubated (40 ⁇ g protein) in reaction buffer (25 mM Hepes, 10% sucrose, 0.1% CHAPS, 10 mM DTT) containing 50 ⁇ M of Z-DEVD-AFC fluorescence substrate at 37 ° C for 1 hour.
  • the separation of the AFC fluorophore was determined in a spectrofluorometer at an excitation wavelength of 400 nm and the fluorescence was detected at an emission wavelength of 505 nm.
  • Caspase 3 activity was expressed as fluorescence units / mg protein / h (Posadas et al., 2009, Pharm. Res., In press).
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • NMDA MK-801 (10 ⁇ M).
  • Example 5 Evaluation of the neuroprotective activity of MTA in an in vitro neuroinflammation model Summary
  • Neuroinflammation is a common process that takes place in several neurological diseases, such as Multiple Sclerosis, Alzheimer's disease, Parkinson's, ALS or stroke, which contribute to neurodegeneration.
  • An in vitro model of neuroinflammation has been developed using organotypic cerebellar cultures stimulated with LPS for the evaluation of the neuroprotective activity of MTA. The results indicate that MTA decreases the number of dystrophic axons and prevents the loss of myelin, confirming the advantageous effect of MTA by protecting axons and myelin against damage mediated by the immune system.
  • LPS lipopolysaccharide
  • Cerebellar organotypic cultures that were previously treated for half an hour with 192 ⁇ M of MTA and 15 ⁇ g / ml of LPS have been used to generate the neuroinflammation model.
  • mice Three groups of animals, each consisting of 5 P8-10 mice.
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • MTA protects against demyelination, a neurodegeneration in this model of neuroinflammation in organotypic cultures.
  • Example 6 MTA neuroprotective activity in axonal damage in a transgenic model of progressive multiple sclerosis
  • MTA has demonstrated cellular protection properties in vitro and in animal models of liver disease.
  • MTA has immunomodulatory properties and is able to improve the evolution and pathogenesis of the animal model of MS, Experimental Autoimmune Encephalomyelitis.
  • MTA prevents axonal loss in the EAE model, suggesting a neuroprotective activity that will be beneficial for the treatment of the disease.
  • transgenic mice expressing fluorescent axons were used in the motor mechanism (the tract corticospinal).
  • Fluorescent motor axon marking allows precise quantification of axonal damage during
  • PBS Placebo
  • MTA was supplied by ENANTIA S. L. (Barcelona, Spain).
  • TLE Temporal lobe epilepsy
  • SE methylthioadenosine
  • pre-SE MTA One group of rats received MTA for 5 days starting 2 days before SE
  • post-MTA SE another group was given MTA for 3 days starting at the end of SE
  • Cell loss was examined in brain sections 3-5 days (initial time point) or 30 days (subsequent time point) after SE.
  • the growth of mossy fibers was also examined by Timm staining at the subsequent time point.
  • a vehicle was administered to a control group and SE was carried out, and a second control group was administered MTA and saline instead of pilocarpine.
  • TLE Temporal lobe epilepsy
  • SE epileptic state
  • TLE normally used that consistently produces epileptic animals with patterns of cell loss and aberrant reorganization very similar to human TLE.
  • mice Young adult male Sprage-Dawley rats (175-200 g) were divided into four MTA treatment groups, 9-11 rats per group.
  • group A the rats were subjected to an epileptic state (SE) induced by pilocarpine. After 90 minutes of continuous seizure activity, the SE was stopped by a single administration of diazepam (10 mg / kg). Rats were injected with vehicle or MTA once daily for 3 days. The rats were sacrificed on day 4 after SE and their brains were fixed by infusion, frozen and sectioned for histology.
  • group B the treatment with rats was the same as in Group A except that the rats were sacrificed on day 30 after SE.
  • group C the rats were treated with Mta once daily for two days.
  • the rats experienced Pilocarpine-induced SE.
  • the rats were continuously treated with MTA once daily for three more days; Controls received placebo.
  • the rats were anesthetized and sacrificed on day 4 after SE:
  • group D the rats were treated in the same manner as group C except that the rats were sacrificed on day 30 after SE. Histology
  • Sections were stained with cresyl violet (Nissl) and immunostained with NeuN to examine cell loss. Staining with Timm to identify the growth of mossy fibers was performed in the 30-day survival group.
  • MTA was supplied by ENANTIA S.L. (Barcelona, Spain).
  • Co-violet cresyl staining showed qualitatively more Nissl stained cells in the hippocampus of rats treated with MTA compared to the vehicle, regardless of whether MTA treatment was initiated before or after SE, at both initial and subsequent time points .
  • the results of immunostaining with NeuN were similar and the examples at the 30-day time point are shown in Figure 17.
  • the differences in Cellular survival were qualitatively clear in the dentate gyrus and the pyramidal cell layers of the hippocampus area CA3 and CAl.
  • the quantification of the Nissl stained cell count in the CAl area is shown in Figure 18. The findings suggest that treatment with MTA is neuroprotective in this epilepsy model.
  • MTA exerts neuroprotective properties in the establishment of neuronal death induced by SE.
  • Parkinson's disease several neuronal populations degenerate leading to a chronic degenerative disease with movement disorders, cognitive abnormalities and vegetative symptoms.
  • the neuronal populations damaged by the disease the most prominent are the dopaminergic neurons of the black substance in the brain stem, affecting the functioning of the basal ganglia.
  • MPTP poisoning l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine
  • MPTP poisoning in humans and animals produces a disease highly reminiscent of Parkinson's disease, both clinically and histologically.
  • Parkinson's disease lacks treatments aimed at modifying the evolution of the disease (disease-modifying drugs), although symptomatic therapy is well developed. Due to its high frequency, health and social cost, the development of new therapies to stop the evolution of the disease is a top priority. In this sense, therapies are aimed at protecting or regenerating dopaminergic neurons, which are mainly recognized by diseases.
  • MTA 30 mg / kg for 5 days.
  • MTA was dissolved in purified water with 2% DMSO at a final concentration of 6 mg / ml and injected intraperitoneally in a dose of 96 ⁇ mol / Kg or 192 ⁇ mol / Kg.
  • MTA was injected 24 hours before the injection of MPTP and for the next four days the administration of MTA was 1 hour before the administration of MPTP.
  • the sections were mounted on glass slides using a 2% solution of gelatin in 0.05M Tris-HCl. The next day they contracted with Nissi (Sigma), were dehydrated, purified on xiiene and coated with DPX. Before the peroxidase inhibition, incubation with the primary and secondary antibodies, peroxidase conjugation and incubation with DAB and mounting on the glass slides, the sections were washed 3 times with 0.125 M PBS. Histological quantification was performed using the system. CAST of Oiympus using e! BX50 microscope and the following methods described by Oorschot (J Comp Neurol 366: 580- 599, 1996).
  • the Cavalieru method was used to calculate the volumes using sections with a thickness of 50 ⁇ m. Neurons were counted using the optical dissector every 3 sections at a distance of 150 ⁇ m and x400. In all cases, the error coefficient was lower than
  • Example 9 Ability of MTA to induce neuronal differentiation in a "/" vitro "model and study of the signaling pathways involved
  • MTA methylioadenosine
  • the PC 12 line is used as a model system for differentiation of neuronal cells.
  • NGF nerve growth factor
  • PC12 cells were maintained at 37 0 C in Ham's supplemented with 2.5% fetal bovine serum, 15% horse serum and penicillin / streptomycin.
  • Neurite differentiation assays were performed in 24-well plates treated with collagen in HAM'S medium supplemented with 0.5% fetal bovine serum and penicillin / streptomycin.
  • NGF 100 ng / ml
  • MTA was added to the cultures at different concentrations (25 ⁇ M, 10 ⁇ M and
  • MTA in the differentiation of neurites may not take the same route of action of
  • NGF pathway that requires inhibition of STAT 3 phosphorylation ( Figure 21).
  • the neuroprotection capacity of MTA in the rat Schawnoma line RN22 was tested against two types of oxidative stress: hydrogen peroxide and copper sulfate. Neuroprotection was measured by the ability to protect against death caused by stress and the ability to reduce the production of reactive oxygen species (ROS) directly related to the production of oxidative stress.
  • ROS reactive oxygen species
  • Line RN22 (Rat Schawnoma) is used as a system for the study of protection against stress due to copper sulfate because in this line NGF is able to activate survival pathways through its p75 membrane receptor. After stress generation, the cells in which NGF is added activate survival pathways through the p75 receptor that allows them to survive the conditions.
  • the stress survival system in RN22 is therefore an ideal system for studying the ability of MTA to protect cells of the nervous system against different types of stress.
  • the RN22 cells were maintained at 37 0 C in DMEM medium supplemented with 10% fetal bovine serum and penicillin / streptomycin.
  • the tests against copper sulfate stress were carried out in 24-well plates in DMEM medium without serum. After allowing the adhesion of the cells for 3 days, NGF (100 ng / ml) or MTA was added at different concentrations half an hour before copper sulfate (150 ⁇ M). After 24 hours, cell viability was quantified by MTT assay and ROS production by fluorescence.
  • the tests against hydrogen peroxide stress were performed in the same manner as above but using 100 ⁇ M hydrogen peroxide as the stress producing agent.
  • the amount of MTT (Sigma) that is reduced to insoluble formazan is determined. After separating the medium, the water-insoluble formazan is solubilized in DMSO and the dissolved material is measured in the spectrophotometer at 570 nm.
  • the amount of ROS produced by the cells after stress with and without treatment was determined.
  • DCFH 7'-Dichlorodihydrofluorescin
  • MTA exerts a significant neuroprotective effect even reaching the levels of protection of the NGF control in most of the concentrations of MTA tested ( Figure 22).
  • the effect of MTA depends on the concentration of the molecule, the concentrations being high
  • MTA neuroprotective capacity against different types of oxidative stress.
  • MTA in both cases maintains cell viability after stress and has an anti-oxidant effect, significantly reducing ROS production levels in Schawn cells.

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  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Molecular Biology (AREA)
  • Psychology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)
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Abstract

La présente invention concerne l'utilisation de la 5-méthylthioadénosine, de ses sels pharmaceutiquement acceptables et/ou de promédicaments de ses derniers, en tant que principe actif dans la fabrication d'un médicament pour la prévention ou le traitement de la mort ou de la détérioration de cellules nerveuses, un médicament neuroprotecteur, un médicament pour la régénération de cellules nerveuses et un médicament pour la prévention ou le traitement d'une maladie neurologique ou psychiatrique. La présente invention porte également sur une méthode de prévention ou de traitement de la mort ou de la détérioration de cellules nerveuses, sur une méthode de neuroprotection, sur une méthode de régénération de cellules nerveuses et sur une méthode de prévention ou de traitement d'une maladie neurologique ou psychiatrique.
PCT/ES2010/070374 2009-06-11 2010-06-07 Propriétés neuroprotectrice de la 5'-méthylthioadénosine Ceased WO2010142827A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2012514499A JP2012529477A (ja) 2009-06-11 2010-06-07 ５’−メチルチオアデノシンの神経保護特性
CN2010800355935A CN102573854A (zh) 2009-06-11 2010-06-07 5’-甲硫腺苷的神经保护特性
CA2762890A CA2762890A1 (fr) 2009-06-11 2010-06-07 Proprietes neuroprotectrice de la 5'-methylthioadenosine
MX2011013311A MX2011013311A (es) 2009-06-11 2010-06-07 Propiedades neuroprotectoras de 5'-metiltioadenosina.
EP10730196A EP2441459A1 (fr) 2009-06-11 2010-06-07 Propriétés neuroprotectrice de la 5'-méthylthioadénosine
AU2010258589A AU2010258589A1 (en) 2009-06-11 2010-06-07 5'-methylthioadenosine neuroprotective properties
US13/376,894 US20120083464A1 (en) 2009-06-11 2010-06-07 Neuroprotective properties of 5'-methylthioadenosine

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ESP200930298 2009-06-11
ES200930298 2009-06-11

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CN (1) CN102573854A (fr)
AU (1) AU2010258589A1 (fr)
CA (1) CA2762890A1 (fr)
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JP6226962B2 (ja) * 2013-04-05 2017-11-08 ライオン株式会社 ノンレム睡眠促進剤、深睡眠促進剤、自然睡眠誘発剤、および睡眠初期デルタパワー向上剤
WO2019236677A1 (fr) * 2018-06-05 2019-12-12 The Regents Of The University Of California Procédés de traitement de dystrophies musculaires
WO2020069934A1 (fr) * 2018-10-05 2020-04-09 University Of Plymouth Composition neuroprotectrice
KR102022118B1 (ko) * 2019-01-07 2019-09-18 주식회사 아스트로젠 중추신경계 질환의 예방 또는 치료용 세린 유도체 화합물
CN113754719B (zh) * 2021-07-08 2023-08-04 荣成泰祥食品股份有限公司 三肽及其在制备改善记忆的药品和保健品中的应用
CN115825314A (zh) * 2021-09-17 2023-03-21 中国科学院深圳先进技术研究院 一种阿尔兹海默症生物标志物s-甲基-5′-硫代腺苷及其应用
CN114515294A (zh) 2022-02-25 2022-05-20 浙江中医药大学 5’-甲基硫代腺苷在制备肥胖抑制药物或保健品中的应用

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EP2441459A1 (fr) 2012-04-18
CA2762890A1 (fr) 2010-12-16
US20120083464A1 (en) 2012-04-05
JP2012529477A (ja) 2012-11-22
AU2010258589A1 (en) 2011-12-15
CN102573854A (zh) 2012-07-11

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